Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
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Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice. / Osterreicher, Christoph H; Taura, Kojiro; Samuele, De Minicis; Seki, Ekihiro; Penz-Osterreicher, Melitta; Kodama, Yuzo; Kluwe, Johannes; Schuster, Manfred; Oudit, Gavin Y; Penninger, Josef M; Brenner, David A.
In: HEPATOLOGY, Vol. 50, No. 3, 3, 2009, p. 929-938.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
AU - Osterreicher, Christoph H
AU - Taura, Kojiro
AU - Samuele, De Minicis
AU - Seki, Ekihiro
AU - Penz-Osterreicher, Melitta
AU - Kodama, Yuzo
AU - Kluwe, Johannes
AU - Schuster, Manfred
AU - Oudit, Gavin Y
AU - Penninger, Josef M
AU - Brenner, David A
PY - 2009
Y1 - 2009
N2 - The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang(1-7) in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (alpha-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl(4)) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang(1-7) receptor Mas and Ang(1-7) inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs. Conclusion: ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang(1-7). Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.
AB - The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang(1-7) in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (alpha-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl(4)) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang(1-7) receptor Mas and Ang(1-7) inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs. Conclusion: ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang(1-7). Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.
KW - Animals
KW - Mice
KW - Angiotensin I pharmacology
KW - Angiotensin II metabolism
KW - Carbon Tetrachloride Poisoning prevention
KW - control
KW - Extracellular Signal-Regulated MAP Kinases metabolism
KW - Gene Deletion
KW - Hepatic Stellate Cells drug effects
KW - Ligation
KW - Liver Cirrhosis prevention
KW - Mice, Knockout
KW - Peptide Fragments pharmacology
KW - Peptidyl-Dipeptidase A genetics
KW - Recombinant Proteins therapeutic use
KW - Renin-Angiotensin System physiology
KW - Animals
KW - Mice
KW - Angiotensin I pharmacology
KW - Angiotensin II metabolism
KW - Carbon Tetrachloride Poisoning prevention
KW - control
KW - Extracellular Signal-Regulated MAP Kinases metabolism
KW - Gene Deletion
KW - Hepatic Stellate Cells drug effects
KW - Ligation
KW - Liver Cirrhosis prevention
KW - Mice, Knockout
KW - Peptide Fragments pharmacology
KW - Peptidyl-Dipeptidase A genetics
KW - Recombinant Proteins therapeutic use
KW - Renin-Angiotensin System physiology
M3 - SCORING: Zeitschriftenaufsatz
VL - 50
SP - 929
EP - 938
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 3
M1 - 3
ER -
